Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D309/06—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention concerns novel aryl derivatives and more particularly novel aryl derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO).
• the invention also concerns processes for the manufacture of said aryl derivatives and novel pharmaceutical compositions containing them.
• Also included in the invention is the use of said aryl derivatives in the treatment of various inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.
• the aryl derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B4 (LTB4) and the peptido-lipid leukotrienes such as leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and various metabolites.
• 5-LO which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B4 (LTB4) and the peptido-lipid leukotrienes such as leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and various metabolites.
• the biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences , 1986, 7 , 100-103.
• the leukotrienes and their metabolites have been implicated in the production and development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, angina and peripheral vascular disease.
• leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function.
• Other physiologically active metabolites of arachidonic acid such as the prostaglandins and thromboxanes, arise via the action of the enzyme cyclooxygenase on arachidonic acid.
• Such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, mediated alone or in part by one or more leukotrienes.
• Ar1 is phenyl or naphthyl which may optionally bear one, two or three substituents selected from amino, halogeno, hydroxy, cyano, carboxy, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, amino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, cyano-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy and di-[(1-4C)
• alkyl includes both straight-chain and branched-chain alkyl groups.
• references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
• An analogous convention applies to other generic terms.
• optically active or racemic forms by virtue of one or more substituents containing an asymmetric carbon atom
• the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO.
• the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
• inhibitory properties against 5-LO may be evaluated using the standard laboratory techniques referred to hereinafter.
• a suitable value for Ar1 when it is naphthyl is, for example, 1-naphthyl or 2-naphthyl.
• Suitable values for substituents which may be present on Ar1 , Ar2 or Ar3 include, for example:-
• a suitable value for X1 when it is (1-4C)alkylimino is, for example, methylimino, ethylimino or propylimino.
• a suitable value for X1 when it is (1-4C)alkylene is, for example, methylene, ethylene, trimethylene or tetramethylene.
• Suitable values for X1 when it is (1-4C)alkylene which bears one or two substituents selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and phenyl include, for example, hydroxymethylene, 1-hydroxyethylene, 2-hydroxyethylene, ethylidene, propylidene, isopropylidene, 1-methylethylene, 2-methylethylene, methoxymethylene, ethoxymethylene, 1-methoxyethylene, 2-methoxyethylene, benzylidene, 1-phenylethylene, 2-phenylethylene, 1-hydroxy-1-methylmethylene, alpha-hydroxybenzylidene, 1-methoxy-1-methylmethylene, 1-ethoxy-1-methylmethylene and alpha-methoxybenzylidene.
• a suitable value for Ar1 when it is a 5- or 6-membered monocyclic heterocyclic moiety or a 9- or 10-membered bicyclic heterocyclic moeity each containing one or two nitrogen heteroatoms and each optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, or a hydrogenated derivative thereof, is, for example, pyrrolyl, pyrrolidinyl, indolyl, pyrazolyl, indazolyl, imidazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, quinolyl, isoquinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, quinazolinyl or cin
• Ar1 is such a heterocyclic moiety which bears one oxo or thioxo substituent, for example, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyridyl, 2-oxo-1,2-dihydroquinolinyl, 4-oxo-1,4-dihydroquinolinyl or 4-oxo-3,4-dihydroquinazolinyl, or the corresponding thioxo derivatives such as 2-thioxo-1,2-dihydropyridyl, which may be attached through any available position including through any available nitrogen atom and which may bear a further substituent including a (1-4C)alkyl substituent on any available nitrogen atom.
• substituent for example, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyridyl, 2-oxo-1,2-dihydroquinolinyl,
• a suitable value for Ar2 and Ar3, which may be the same or different, when each is phenylene is, for example, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene.
• a suitable value for R1 when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl or butyl; when it is (3-4C)alkenyl is, for example, allyl, 2-butenyl or 3-butenyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl.
• R2 and R3 together form a group of the formula -A1 -X3-A2-which together with the carbon atom to which A1 and A2 are attached define a ring having 5 to 7 ring atoms then a suitable value for A1 or A2, which may be the same or different, when each is (1-3C)alkylene is, for example, methylene, ethylene or trimethylene.
• Suitable values for the substituents which may be present on said 5- to 7-membered ring include for example:-
• a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
• a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• novel compounds of the invention include, for example, aryl derivatives of the formula I wherein:-
• a further particular compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is phenyl which may optionally bear one or two substituents selected from fluoro, chloro, hydroxy, cyano, trifluoromethyl, methyl, ethyl, tert -butyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, hydroxymethyl, 2-hydroxyprop-2-yl, carboxymethyl, 1-carboxyethyl, 2-carboxyprop-2-yl, carboxymethoxy, 1-carboxyethoxy, 2-carboxyprop-2-yloxy, 2-dimethylaminoethoxy and 3-dimethylaminopropoxy;
• X1 is oxy, thio, sulphinyl, sulphonyl, difluoromethylene, imino, methylene, hydroxymethylene, ethylidene, methoxy
• a further particular compound of the invention comprises an aryl derivative of the formula I as defined immediately hereinbefore wherein Ar1 may optionally bear one or two further substituents selected from methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl. dimethylaminomethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl; or a pharmaceutically-acceptable salt thereof.
• a further particular compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is phenyl which may optionally bear one or two substituents selected from fluoro, chloro, hydroxy, carboxy, trifluoromethyl, methyl, ethyl, tert -butyl, methoxy, ethoxy, hydroxymethyl, 2-hydroxyprop-2-yl, carboxymethyl, 1-carboxyethyl, 2-carboxyprop-2-yl, carboxymethoxy, 1-carboxyethoxy, 2-carboxyprop-2-yloxy and 2-dimethylaminoethoxy;
• X1 is thio, sulphinyl, sulphonyl, difluoromethylene, methylene, ethylene, hydroxymethylene, ethylidene, methoxymethylene, benzylidene, 1-hydroxy-1-methylmethylene, alpha-hydroxybenzylidene or 1-methoxy-1-methylmethylene, or X1 is a
• a further particular compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is phenyl which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, tert -butyl, methylamino, dimethylamino, aminomethyl, carboxymethoxy, 2-dimethylaminoethoxy and 3-dimethylaminopropoxy; X1 is oxy, thio, sulphinyl, sulphonyl, difluoromethylene, imino, oxymethylene, methylene, hydroxymethylene, ethylidene, methoxymethylene, benzylidene, 1-hydroxy-1-methylmethylene, alpha-hydroxybenzylidene or 1-methoxy-1-methylmethylene; Ar2 is 1,4-pheylene which may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy; X2 is oxy,
• a further particular compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is phenyl which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl, ethyl and tert -butyl; X1 is thio, sulphinyl, sulphonyl, difluoromethylene, oxymethylene, methylene, ethylene, hydroxymethylene, ethylidene, methoxymethylene, benzylidene, 1-hydroxy-1-methylmethylene, alpha-hydroxybenzylidene or 1-methoxy-1-methylmethylene; Ar2 is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy; X2 is thio; Ar3 is 1,3-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl and methyl; R1 is methyl or ethyl
• a further particular compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is 1-pyrrolyl-1, 1-pyrazolyl, 3-pyridyl, 2-oxo-1,2-dihydropyrid-1-yl or 4-oxo-1,4-dihydropyrid-1-yl; X1 is a direct link to Ar2, or X1 is carbonyl or methylene; Ar2 is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy; X2 is thio; Ar3 is 1,3-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl and methyl; R1 is methyl or ethyl; and R2 and R3 together form a group of the formula -A1-X3-A2- which together with the carbon atom to which A1 and A2 are attached define a ring having 6 ring atoms, wherein A1 is
• a preferred compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-dichlorophenyl or 4-dimethylaminophenyl; X1 is oxy, thio, oxymethylene, methylene, ethylidene or difluoromethylene; Ar2 is 1,4-phenylene or 2-chloro-1,4-phenylene; X2 is thio; Ar3 is 1,3-phenylene or 5-fluoro-1,3-phenylene; R1 is methyl; and R2 and R3 together form a group of the formula -A1 -X3-A2- which together with the carbon atom to which A1 and A2 is attached define a ring having 6 ring atoms, wherein A1 is ethylene, A2 is ethylene and X3 is oxy, and which ring may bear a methyl substituent alpha to X3;
• a further preferred compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is 4-fluorophenyl, 2,4-difluorophenyl or 2,6-dichlorophenyl; X1 is oxymethylene, methylene, ethylidene or difluoromethylene; Ar2 is 1,4-phenylene; X2 is thio; Ar3 is 1,3-phenylene or 5-fluoro-1,3-phenylene; R1 is methyl; and R2 and R3 together from a group of the formula -A1-X3-A2- which together with the carbon atom to which A1 and A2 is attached define a ring having 6 ring atoms, wherein A1 is ethylene, A2 is ethylene and X3 is oxy, and which ring may bear a methyl substituent alpha to X3; or a pharmaceutically-acceptable salt thereof.
• a further preferred compound of the invention comprises an aryl derivative of the formula I wherein Ar1 is 1-pyrrolyl or 3-pyridyl; X1 is a direct link to Ar2, or X1 is carbonyl or methylene; Ar2 is 1,4-phenylene; X2 is thio; Ar3 is 1,3-phenylene or 5-fluoro-1,3-phenylene; R1 is methyl; and R2 and R3 together form a group of the formula -A1 -X3-A2- which together with the carbon atom to which A1 and A2 is attached define a ring having 6 ring atoms, wherein A1 is ethylene, A2 is ethylene and X3 is oxy, and which ring may bear a methyl substituent alpha to X3; or a pharmaceutically-accpetable salt thereof.
• a specific especially preferred compound of the invention is, for example, the following aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof:- 4-[3-(4-(4-fluorobenzyl)phenylthio)phenyl]-4-methoxytetrahydropyran, 4-[3-(4-(2,4-difluorobenzyl)phenylthio)phenyl]-4-methoxytetrahydropyran, 4-[3-(4-(4-fluoro-alpha-methylbenzyl)phenylthio)phenyl]-4-methoxytetrahydropyran, 4-[3-(4-(4-fluorophenoxymethyl)phenylthio)phenyl]-4-methoxytetrahydropyran, 4-(5-fluoro-3-(4-(4-fluoro-alpha,alpha-difluorobenzyl)phenylthio)phenyl]-4-methoxyt
• a further specific especially preferred compound of the invention is, for example, the following aryl derivative of the formula 1, or a pharmaceutically-acceptable salt thereof:- 4-methoxy-4-[3-(4-pyrrol-1-ylmethyl)phenylthio)phenyl]tetrahydropyran.
• a compound of the invention comprising an aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, Ar1 , X1, Ar2, X2, Ar3, R1, R2 and R3 have any of the meanings defined hereinbefore.
• a suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, iodo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
• a suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (1-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.
• the coupling reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
• reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)-palladium, cuprous chloride or cuprous bromide.
• a suitable catalyst for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)-palladium, cuprous chloride or cuprous bromide.
• a suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group (especially acetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert -butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl).
• the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or alkoxycarbonyl or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an acyl group such as a tert -butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
• a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a (1-4C)alkyl group (especially methyl or ethyl) which may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide; or, for example, a tert -butyl group which may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide
• a tert -butyl group which may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
• a suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl).
• the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
• the starting materials of the formula Ar1 -X1-Ar2-X2-H and of the formula II may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
• the intermediate of the formula II may conveniently be obtained from the compound of the formula Z-Ar3-Y, as defined hereinbefore, by reversing the order of introduction of the groups R2 and R3 which is used in Scheme I.
• the coupling reaction is conveniently performed in a suitable inert solvent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
• the reaction may conveniently be performed in the presence of a suitable catalyst as defined hereinbefore.
• the starting materials of the formula Ar1 -X1 -Ar2-Z and of the formula III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples which are provided for the purpose of illustration only. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated in accompanying Scheme II (set out hereinafter) or by modifications thereto which are within the ordinary skill of an organic chemist.
• a suitable protecting group R4, as employed in Scheme II, is any one of the many such groups known in the art and includes any appropriate protecting group as defined hereinbefore. Examples of such groups are given in Scheme II. The conditions for the introduction and removal of such protecting groups are described in standard textbooks of organic chemistry such as, for example, "Protective Groups in Organic Synthesis” by T W Green (J Wiley and Sons, 1981).
• the alkylation reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 100°C, conveniently at or near ambient temperature.
• the tertiary alcohol starting material of the formula IV may be obtained by standard procedures of organic chemistry. Conveniently, and as illustrated in accompanying Scheme III (set out hereinafter), intermediates of the formulae Ar1-X1-Ar2-X2-Ar3-Y, wherein Ar1, X1, Ar2, X2 and Ar3 have the meanings defined hereinbefore and Y is, for example, a halogeno, formyl, alkanoyl, nitrile or alkoxycarbonyl group may be utilised in the preparation of the tertiary alcohol starting material of the formula IV.
• a suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate), chromium trioxide or gaseous oxygen in the presence of platinum.
• the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups.
• the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert -butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C.
• a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol.
• a compound of the formula I containing a sulphonyl group it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound.
• a phamaceutically-acceptable salt of a novel compound of the formula I When a phamaceutically-acceptable salt of a novel compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.
• an optically active form of a compound of the formula I it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure.
• novel compounds of the formula I are inhibitors of the enzyme 5-LO.
• the effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:-
• the compound 4-[3-(4-(4-fluorobenzyl)phenylthio)phenyl]-4-methoxytetrahydropyran has an IC50 of 0.04 ⁇ M against LTB4 in test a), and an oral ED50 of 2mg/kg versus LTB4 in test c); and the compound 4-[5-fluoro-3-(4-(4-fluoro-alpha,alpha-difluorobenzyl)phenylthio)phenyl]-4-methoxytetrahydropyran has an IC50 of 0.14 ⁇ M against LTB4 in test a), and an oral ED50 of 1 mg/kg versus LTB4 in test c).
• those compounds of the formula I which are particularly preferred have an IC50 of ⁇ 1 ⁇ M against LTB4 in test a), and an oral ED50 of ⁇ 100 mg/kg against LTB4 in tests b) and/or c).
• These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-LO as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin.
• a pharmaceutical composition which comprises an aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
• the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository: for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
• the above compositions may be prepared in a conventional manner using conventional excipients.
• the amount of active ingredient (that is an aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
• a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
• Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
• the invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above.
• the invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
• compounds of the formula I are useful in treating those allergic and inflammatory conditions which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-LO catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-LO.
• such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders of an inflammatory nature, arthritic and inflammatory joint disease, and inflammatory bowel diseases.
• a daily dose in the range for example, 0.5mg to 75mg per kg body weight is received, given if required in divided doses.
• a parenteral route is employed.
• a dose in the range for example, 0.5mg to 30 mg per kg body weight will generally be used.
• a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
• the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the enzyme 5-LO. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
• the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non-steroidal anti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam.
• NSAIA cyclooxygenase inhibitory non-steroidal anti-inflammatory agents
• co-administration of a 5-LO inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects.
• a pharmaceutical composition which comprises an aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier.
• cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats.
• compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment.
• a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition.
• an anti-histamine, steroid such as beclomethasone dipropionate
• sodium cromoglycate sodium cromoglycate
• phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition.
• the aqueous phase was acidified to pH4 by the addition of dilute aqueous hydrochloric acid solution and extracted with diethyl ether (2 x 10 ml). The combined organic extracts were dried (MgSO4) and evaporated. There was thus obtained the required starting material as an oil (0.5 g) which crystallised on standing and was used without further purification.
• a solution of sodium nitrite (0.6 g) in water (4 ml) was added dropwise to a stirred solution of a portion (2 g) of the material so obtained in a mixture of concentrated hydrochloric acid (20 ml) and water (4 ml) which had been cooled to 0° to 5°C.
• the mixture was stirred at 0° to 5°C for 15 minutes and then added to a stirred solution of potassium iodide (3.2 g) in water (20 ml) which had been cooled to 0° to 5°C.
• the mixture was allowed to warm to ambient temperature and was stirred for 16 hours.
• the mixture was extracted with ethyl acetate (3 x 40 ml).
• Pyridine-borane complex (0.2 ml, 2 equivalents) was added to a solution of a portion (0.384 g) of the material so obtained in trifluoroacetic acid (2 ml) and the mixture was stirred at ambient temperature for 16 hours and then heated to reflux for 40 minutes. The mixture was cooled to ambient temperature and evaporated. The residue was basified by the addition of a strong aqueous sodium hydroxide solution and the aqueous mixture was heated to 120°C for 30 minutes. The mixture was cooled to ambient temperature and extracted with diethyl ether (3 x 30 ml). The combined extracts were washed with water, dried (Na2SO4) and evaporated.
• a Grignard reagent was prepared from 3,5-difluorobromobenzene (38.6 g) and magnesium (4.88 g) in a mixture of toluene (100 ml) and THY (50 ml) using the following method.
• the 3,5-difluorobromobenzene was dissolved in toluene (50 ml) and a portion (aprox. 5%) of the solution was added to a stirred suspension of the magnesium in a mixture of toluene (50 ml) and THY (50 ml).
• the mixture was stirred at ambient temperature for approximately 40 minutes until the initiation of the exothermic formation of the Grignard reagent was observed.
• the mixture was cooled in an ice-bath to a temperature in the range 15 to 20°C while the remainder of the solution of 3,5-difluorobromobenzene was added.
• the mixture was stirred at ambient temperature for 2 hours.
• Tetrahydropyran-4-one (10.69 g) was added over 1 hour to a portion (100 ml) of the Grignard reagent so obtained which was cooled to a temperature in the range 15 to 20°C. The mixture was stirred at ambient temperature for 2 hours. The mixture was cooled in an ice-bath and aqueous hydrochloric acid solution (50% w/v, 25 ml) and brine (30% w/v, 52 ml) were added in turn. The toluene layer was separated and the aqueous layer was extracted with toluene (32 ml). The organic solutions were combined and washed with water (4 x 32 ml). The solution was evaporated under reduced pressure to a volume of 16.3 ml.
• Lithium aluminium hydride (1M in THF. 1.5 ml) was added dropwise to a stirred solution of 4-[3-(4-(4-cyanobenzyl)phenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran (0.675 g) in THF (9 ml) and the mixture was stirred at ambient temperature for 1 hour.
• Water (5 ml) and 4N aqueous sodium hydroxide solution (5 ml) were added in turn.
• the mixture was extracted with diethyl ether.
• the organic phase was washed with water, dried (MgSO4) and evaporated.
• the 2-chloro-4-dimethylamino-4′-iododiphenylmethane used as a starting material was obtained using similar procedures to those described in Example 1 for the preparation of 4-fluoro-4′-iododiphenylmethane except that 2-chloro-4-dimethylaminobenzaldehyde (French Patent Application No. 1,377,226) was used in place of 4-fluorobenzaldehyde. There was thus obtained the required starting material in 30% yield. NMR Spectrum 2.9(s, 6H), 3.9(s, 2H), 6.5-7.6(m, 8H).
• n-Butyl lithium (1.6M in hexane, 2.18 ml) was added dropwise to a stirred suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide (1.44 g) in THF (10 ml) which had been cooled to 0°C. The mixture was stirred at 0°C for 30 minutes. A solution of 4-formyl-4′-iododiphenyl ether (1.13 g) in THF (15 ml) was added and the mixture was stirred at 0°C for 15 minutes and at ambient temperature for 90 minutes. The mixture was partitioned between diethyl ether and water.

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• 1991
  • 1991-11-05 IE IE386691A patent/IE913866A1/en not_active Application Discontinuation
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• 1993
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